Iron Deficiency Anemia
Heather Escoto, MD
Pediatric Hematology/Oncology
Children’s Center for Cancer and Blood Diseases at St. Vincent
Disclosures
Nothing to disclose
Objectives
Review of the following:
1. The definitions and classifications of anemia and
factors affecting hemoglobin levels
2. The function, mechanisms of absorption, transport,
and storage of iron
3. The incidence, risk factors, and etiology of iron
deficiency
4. Physical exam findings, laboratory values, staging,
and differential diagnosis of iron deficiency and iron
deficiency anemia
5. AAP Screening recommendations, prevention, and
treatment of iron deficiency
6. Effects of iron deficiency and iron deficiency anemia
“Anemia 101”
Definition
Classification
.
Definitions of Anemia
Physiologic definition:
-Hemoglobin too low to meet
oxygenation demands
Laboratory definition:
-Hemoglobin at least 2 standard
deviations below mean value based
on age, gender, and race
**Laboratory definition of anemia does
not always agree with physiologic
definition of anemia!
Factors that affect
hemoglobin levels
•
•
•
•
•
•
.
Age
Sex
Race
Puberty
Altitude
Heredity
Hemoglobin levels in
infants- the physiologic
nadir
Term infant
-nadir- 12 weeks of age
-hemoglobin 9.5 gm/dL at nadir
Premature infant
- nadir- 6-8 weeks of age
-hemoglobin 7.0 gm/dL at nadir
-nadir earlier and lower!!!
.
Age specific
Hemoglobin levels
Age
26-30 week
28 week
32 week
Term (cord)
1-3 day
2 week
1 month
2 month
6 month
6 mo-2 year
2 year-6 year
Hgb (g/dL)
13.4 (11)
14.5
15.0
16.5 (13.5)
18.5 (14.5)
16.6 (13.4)
13.9 (10.7)
11.2 (9.4)
12.6 (11.1)
12.0 (10.5)
12.5 (11.5)
Data from Table 14.1, the Harriet Lane Handbook: A manual for pediatric house officers/ the
Harriet Lane Service, Children’s Medical and Surgical Center of the Johns Hopkins Hospital;
editors, Jason Custer, Rachel Rau-18th edition.
Age specific
Hemoglobin levels
(cont.)
Age
Hgb (g/dL)
2 year- 6 year
12.5 (11.5)
6 year-12 year
13.5 (11.5)
12-18 year (male)
14.5 (13)
12-18 year (female) 14.0 (12)
Data from Table 14.1, the Harriet Lane Handbook: A manual for pediatric house officers/ the
Harriet Lane Service, Children’s Medical and Surgical Center of the Johns Hopkins Hospital;
editors, Jason Custer, Rachel Rau-18th edition.
Age and Hemoglobin
levels
Hemoglobin and mean conpuscular volume (MCV) percentile curves for girls and boys.
(Redrawn from Dallman PR, Siimes MA: Percentile curves for hemoglobin and red cell volume
in infancy and childhood. J Pediatr 1979; 94:28.)
Mean Hgb g/dL
Hemoglobin differences
between African-American
and Caucasian children
Males
Females
Data from: Dallman et al. Hemoglobin concentration in white, black and Oriental children: is
there a need for separate criteria in screening for anemia? Am. J. Clin. Nutr.:1978; 31: 377-380.
Sexual Maturity and
Hematocrit
Daniel et al. Hematocrit: maturity relationship in adolescence.
Pediatrics 1973;52:388–394.
Sexual Maturity and
Hematocrit
Daniel et al. Hematocrit: maturity relationship in adolescence.
Pediatrics 1973;52:388–394.
Heredity and
Hemoglobin
Siimes et al, J Pediatr 1994 Jan;124(1):100-2. Effect of Hereditary on Hemoglobin
Concentration.
Basic Laboratory
Evaluation of Anemia
1. Complete blood count
2. Red blood cell indices- MCV,
MCHC, RDW
3. Reticulocyte count
4. Peripheral smear-red cell
morphology
5. Other labs as clinically indicatediron studies, electrophoresis,
hemolytic workup, Coombs
Quote or statistic could go here. Either the same one throughout, or change from page to page.
Reticulocyte count and
anemia
Reticulocyte
Reticulocyte countabsolute and percentage
Reticulocyte count (percentage)- % of absolute concentration of RBCs containing
precipitated RNA (reticulin)
-non-invasive measure of new red cell production by
bone marrow
-dependent on RBC count
-overestimated with severe anemia
Absolute reticulocyte count
% Reticulocytes X RBC count/100
Hgb 6.4 - 3% X 2,080,000 /100=ARC 62,400
Hgb 11.2 - 3% X 3,470,000 /100= ARC 104,100
.
Physiologic response
to anemia
Increased heart rate
Increased stroke volume
Vasodilation
Decreased oxygen affinity (right shift in
oxygen-hemoglobin dissociation
curve)
Classification of Anemia
Mechanism-Decreased production
-Hemolysis
-Blood loss
RBC size-Microcytic
-Macrocytic
-Normocytic
.
Classification of anemia
MechanismDecreased production
-Marrow infiltration-malignancy
-Marrow injury- infections, toxins
-Nutritional deficiency
-Ineffective erythropoesis
(thalassemias)
-Erythropoietin deficiency
-Labs: Low reticulocyte count,
variable MCV
Classification of anemia
Blood loss-Reticulocyte count usually elevatedbone marrow trying to compensate
-MCV usually normal to slightly elevated
Hemolysis-Acquired
-autoimmune process, vessel injury,
-Inherited RBC defect
-Reticulocyte count usually elevated
-MCV normal to slightly elevated
Classification of anemiamorphology
Microcytic
-Iron deficiency
-Thalassemia
-Chronic disease
-Copper deficiency
Macrocytic
-Folate deficiency
Normocytic
-Chronic disease
-Malignancy
-Renal failure
-Blood loss
-Hemolytic disorders
-Hemoglobinopathies
-Vitamin B12 deficiency
-Inherited bone marrow failure
-Hypothyroidism
-Drug induced
-Active hemolysis
Quote or statistic could go here. Either the same one throughout, or change from page to page.
Iron Deficiency
Anemia
.
Why is iron deficiency
important?
• Remains most common nutrient deficiency in
developing countries
• Over 1 billion people affected, nearly half of the
world’s young children
• Decline in prevalence in industrialized countries- but
still common
• In US, most common in lower income infants and
toddlers 12-36 months of age and teenage girls
• Over 700,000 toddlers affected in the US, 1/3 with
anemia, over 7.8 million adolescent females/women
• Long term effects on neurodevelopment, behavior,
neurotransmitter myelination, energy metabolism
• Increased susceptibility to lead toxicity
Why is Iron important?
-Essential component of
hemoglobin and myoglobin
-Component of certain proteins
important for respiration and
energy metabolism
-Component of enzymes involved
in the synthesis of collagen and
some neurotransmitters
-Essential for normal immune
function
Iron: too much is bad
• Generates free radicals
• Causes oxidative damage to cells
Protective mechanisms
• Intracellular and intravascular iron
bound to carrier proteins- transferrin,
ferritin, hemoglobin, etc.
• Iron absorption tightly regulated
Iron overload- most commonly from
chronic transfusions: 1ml PRBCs
has 1 mg iron
.
Iron: How much do we
need?
Preterm infants: 2-4 mg/kg/day
Full term infants: 1 mg/kg day
Children 1-3 years old: 7 mg/day
Children 4-8 years old: 10 mg/day
Children 9-13 years old: 8 mg/day
Males 14-18: 11 mg/day
Females 14-18: 15 mg/day
Food and Nutrition Board of the Institute of Medicine. Iron in: Dietary reference intakes for
Vitamin A, Vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum,
nickel, silicon, vanadium, and zinc. National Academy Press, Washington DC, 2000; p. 339.
Iron distribution in
the body
Hemoglobin
- 4 globin chains (2 alpha and 2 beta
globin chains)
- 4 heme molecules with iron in the
center
Hemoglobin
Heme molecule
Ferritin
• Intracellular protein that stores and
releases iron in a controlled fashion
• Aggregates of ferritin form hemosiderin
• Ferritin is also an acute phase reactantacts to protect iron from being used by an
infective agent
Fe3+
apoferritin
Ferritin
Fe 2+
Iron containing enzymes
-Important
in oxidative metabolism and DNA
synthesis
Heme proteins:
-Cytochromes
-Catalase
-Peroxidase
-Cytochrome oxidase
Flavoproteins:
-Cytochrome C reductase
-Succinic dehydrogenase
-NADH oxidase
-Xanthine oxidase
.
Iron Balance
• Intake= 10 mg/day
• Absorption= 1 mg/day- variable
• Loss- 1 mg/day- mainly by sloughing
of enterocytes (and menstruation in
females)
• Iron stored in macrophages and
hepatocytes
Iron absorption
• 10% of dietary iron is absorbed
• Absorption depends on:
-dietary iron content
- bioavailability (heme vs. nonheme)
- mucosal cell receptor number
• Main absorption occurs in
duodenum
.
Iron absorption
-Heme (meat) >> non-heme iron
sources
-(30%-50% vs. <10%)
-Ferrous sulfate >> ferric sulfate
-Enhanced by red meat, ascorbic acid,
breast milk
-Diminished by vegetable fiber, cow
milk, egg yolk, tea, phytates,
phosphates (soda)
Iron absorption
• Iron is converted from Fe3+ to Fe2+ by
ferrireductase
• Fe2+ transported across mucosal
surface of enterocyte by DMT1,
stored as ferritin
• Ferritin releases Fe2+ which is
transported across basolateral
surface of enterocyte with help of
ferroportin *****
• Fe2+ converted back to Fe3+ by
Hephaestin
• Fe3+ binds to transferrin in plasma
Iron absorption
.
Ferroportin and Hepcidin
Hepcidin
-Blocks ferroportin
-Prevents absorption of iron from enterocytes
-Prevents iron exportation from macrophages
-Increased in inflammation
-Leads to reduced serum iron, microcytic anemia,
and incomplete response to iron therapy
Ferroportin
-Transporter protein in enterocytes and
macrophages
-Blocked by hepcidin
Iron uptake by the
erythroblast
• Fe3+ bound to transferrin attaches to
transferrin receptor on erythroblast
• Transferrin and Fe3+ separate, Fe3+
combines with heme to make
hemoglobin
• Extra Fe stored as ferritin
• Apotransferrin exported out of
erythoblast
Iron uptake by the
erythroblast
Fe3+
Binding of irontransferrin to its
receptor
Release of
apotransferrin
TfR
Incorporation into
iron-protein
Release of iron to
storage
to storage
Ferritin
Hemosiderin
Katz JH. Iron and protein kinetics studied by means of doubly labeled human crystalline
transferrin. J Clin Invest 1961;40:2143-2152.
Iron deficiencydefinitions
Iron deficiency (ID)- deficient in iron, no
anemia
Iron deficiency anemia (IDA)- deficient in
iron leading to anemia
Anemia- 2 SD below defined “normal” mean
based on age and gender
Incidence of ID and
IDA in US
Infants
-no national statistics on incidence of ID and IDA in
infants before 1 year of age
-Norwegian cohort showed 4% incidence at 6
months increasing to 12% incidence at 12 months
Toddlers (1-3 years)
Iron deficiency- 9%-15%
Iron deficiency anemia- 3-5%
Children
Iron deficiency- 4% incidence
•Looker AC, et al. Prevalence of iron deficiency in the United States. JAMA. 1997;277(12):973976.
•Hay et al. Iron status in a group of Norwegian Children aged 6-24 months. Acta Paediatr.
2004;93(5): 592-598.
Incidence of ID and IDA
in US adolescents
Adolescent females
Iron deficiency- 9-11%
Iron deficiency anemia- 2-5%
Adolescent males
Iron deficiency < 1%
Looker AC, et al. Prevalence of iron deficiency in the United States. JAMA. 1997;277(12):973976.
Prevalence of iron deficiency
in US children 1-3 years old
Hispanic- 12%
African American- 6%
Caucasian- 6%
English speaking- 7%
Non-English speaking- 14%
Overweight-20%
Normal weight-7%
Daycare- 5%
No daycare- 10%
Bottle fed <12 months -3.8%
Bottle fed >24 months- 12.4%
Brotanek et al. Iron Deficiency in Early Childhood in the United States: Risk Factors and
Racial/Ethnic Disparities. Pediatrics 2007;120;568. Arch Pediatr Adolesc Med 2005; 159:10381042.
Risk factors for Iron
Deficiency in Infants and
Children
-Prematurity or low birthweight
-Exclusively breastfeeding beyond 4-5
months without iron supplementation
-Cows milk before 1 year
-Excessive milk intake
-Obesity
-Poverty/Low socioeconomic status
-Malnutrition
-Chronic illness or special health needs
Brotanek et al. Iron Deficiency in Early Childhood in the United States: Risk
Factors and Racial/Ethnic Disparities. Pediatrics 2007;120;568
Pizzaro et al. Iron status with different infant feeding regimens: relevance to
screening and prevention of iron deficiency. J Pediatr. 1991 May;118(5):687-
•
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Risk Factors for iron
deficiency in
Adolescents
Growth spurts
Heavy menses
Chronic illness
H pylori infection
Endurance training
Vegetarian diets
Obesity
Poverty
Pregnancy
Etiology of Iron
Deficiency
• Low birth stores
• Dietary- not enough intake
to meet requirements
• Blood loss- majority of iron
stored in RBCS
• Poor absorption
Newborn Iron Stores
• Endowed with 75 mg/kg of iron at birth
• Dependent on hemoglobin concentration at
birth (majority of iron in circulating RBCs)
• Minimally dependent on maternal iron
status
• Depleted by 3 months in low birth weight
infants without supplementation
• Depleted by age 5-6 months in term infants
• Delayed cord clamping (by 2 minutes) leads
to higher ferritin and iron stores at 6 months
of age
Dietary iron content
Milk
• Breast milk
• Whole cow
• Skim
• Formula (low iron)
• Formula (high iron)
mg Fe/Liter
0.5-1 **
0.5-1
0.5-1
2- 4
10-12
Foods
• Infant cereal
• Baby foods
mg/serving
6
0.3-1.2
**more bioavailable
Iron content of Common
Toddler foods/drinks
Foods
• Fruit snacks
• Chicken nuggets
• Macaroni and cheese
• Chips
• Graham crackers
• Cheerios
• Goldfish
Drinks
• Apple juice
• Pediasure
• Soda
% daily
value/serving
0 mg
8%
10%
5%
17%
25%
2%
% daily value
5%
15%
0%
Cows milk and iron
deficiency
• Poor source of iron
• Poor absorption (5-10%)
• Reduces consumption of other
foods, especially with
overconsumption
• Can cause microscopic GI
bleeding
.
Iron rich foods
Heme iron (better bioavailability)
Meat (beef and turkey best)
Shellfish
Non-heme iron (less bioavailability)
Breakfast cereal (iron fortified)
Pasta (iron fortified)
Beans and lentils
Baked potato with skin
Foods that increase iron absorption
Fruits, vegetables, meat, fish,
poultry, white wine
.
Causes of Iron deficiency:
Blood Loss
•GI blood loss:
-cow’s milk, IBD, esophageal
varices, ulcers, anatomic lesions,
parasitic infections
•Menorrhagia
•Epistaxis
•Other rare causes:
pulmonary, renal, intravascular
Iron Deficiency:
Malabsorption
•
•
•
•
•
Short gut
Celiac disease
Medications (GERD)
Chronic Giardiasis
IRIDA (Iron Refractory Iron
deficiency anemia)
• Dx: Iron absorption test
Diagnosis: History
and Physical
History
• blood loss?
• dietary history
• GI symptoms?
• Heavy menses?
• Irritability?
• Weakness?
• PICA?
Physical exam• pallor, tachycardia, irritability
PICA
PICA
PICA and iron
deficiency
• Compulsive ingestion of usually a
single non-nutritive substance
• Behavior cured with therapeutic iron
therapy
Typical ingested substances
Rocks
Carpet
Dirt
Hair
Paint chips
Clothing
Cardboard
Insects
Clay
Ice chips
Lead and iron
deficiency
• Iron deficiency
PICA
• PICA
lead ingestion
• Iron deficiency increases lead
absorption from intestine
• Lead toxicity does not
cause microcytic anemia
Diagnosis of Iron
Deficiency:
Staging
Depletion of
iron stores
Iron deficient
erythropoiesis
Iron
deficiency
anemia
3 stages of Iron
Deficiency
>11
>11
>11
<11
FIG. 4.5. Measurements of Iron Status in Relationship to Body Iron Stores (mg). J.D. Cook and
C.A. Finch, "Assessing Iron Status of a Population," A J. Clin Nutr, 32: 2115 (1979) Graph in
Methods for the Evaluation of the Impact of Food and Nutrition Programmes (UNU, 1984, 287
pages).
Diagnosis of Iron Deficiency:
Laboratory Workup
Laboratory
Ferritin
Serum iron
Serum transferrin (TIBC)
Transferrin saturation ratio (Fe/TIBC)
Hemoglobin
MCV
RDW
Reticulocyte count
Value
<12 µg/dL
<40 µg/dL
>400 µg/dL
<10%
<11 g/dL
<70 fl
>16%
<1%
Diagnosis of Iron Deficiency:
Laboratory Workup
Other supporting labs:
-Platelet count
-Serum transferrin receptor
-Reticulocyte hemoglobin content **
-Hemoglobin A2
-Free erythrocyte protoporphyrin
Hepcidin
C reactive protein
**first laboratory test abnormal
elevated
>35
<26
reduced
>100
reduced
Diagnosis:
peripheral smear
Hypochromia
Microcytosis
Thrombocytosis
l
Differential diagnosis of
microcytic/hypochromic
anemia
Iron deficiency
Thalassemia
Inflammation
Hemoglobin C or Hemoglobin E
disease
Hereditary hyropoikilocytosis
Copper deficiency
Sideroblastic anemia
Congenital atransferrinemia
Laboratory parameters in
thalassemia trait and iron
deficiency
Parameter
α thal
trait
Β thal trait
IDA
Hemoglobin
(g/dL)
12.6
11.3
10.2
Red cell count
(X10^6/µL
5.6
4.7
4.67
MCV (fl)
65.5-72.2
60.8
67
20.3
21.8
MCHC
23.2
HgB A2
Normal or
decreased
Mentzer index
(MCV/RBC
<13
Elevated
Normal or
decreased
>13
Nathan and Oski’s Hematology of Infancy and Children, 7th ed. p.1054 table 20.7
Differential Diagnosis of
Microcytic Hypochromic
Anemia
Anemia of inflammation
Iron restricted erythropoesis:
- Secondary to inflammation, chronic kidney
disease, aging, chemotherapy, IRIDA
- Due to sequestration of iron in macrophages
- Increased hepcidin
- Low serum iron
- Low transferrin saturation
- Normal or increased iron stores
Goodenough et al, Blood 2010; 116:4754-4761
*increased hepcidin blocks
release of iron from macrophages
Differential Diagnosis
of Low Serum Iron
-Iron deficiency
-Infection
-Inflammation
-Malignancy
-Postoperative
-Stress
.
Screening for iron
deficiency
AAP recommendations:
Determination of hemoglobin concentration
-Term infants - 12 months of age
-Preterm infants - 9 months of age
Assessment of risk factors for ID/IDA:
-Inadequate iron intake, poor nutrition,
feeding problems, poor growth
Additional screening at 18-24 months of age?
Pediatrics 2010; 126:1040-1060
Screening for Iron
Deficiency Anemia in
Adolescents
AAP recommendations:
-Menstruating girls be screened
annually by measuring hemoglobin
concentration
-Adolescent boys- screened once
during peak growth period
-Consider risk factors for anemia and
screen appropriate patients at any
time
Committee on Nutrition, American Academy of Pediatrics. Screening for Iron Deficiency, in:
Pediatric Nutrition Handbook, 6th ed, Kleinman, RE (ED). American Academy of Pediatrics, Elk
Grove Village, IL 2009. p. 419
Prevention of Iron
Deficiency Anemia in
Infants and Toddlers
• Breastfeeding for the first 6 months of life
• Iron fortified formula
• Iron fortified infant cereal beginning at 6
months of age
• Iron supplementation for preterm infants
• Iron supplementation for breastfeeding
infants at 4 months of age
• Avoid cows milk before 1 year of age
• Limit cows milk intake to 18-24 oz/day after
12 months of age
Iron DeficiencyTreatment
Oral iron therapy
• Mild iron deficiency- 3 mg/kg/d
elemental iron in daily dose
• Moderate to severe- 6 mg/kg/d
elemental iron divided twice daily
• Severe- consider PRBC transfusion
(Hgb <4 gm/dl) AND oral iron
.
Types of Oral iron
Ferrous sulfate
- 20 % elemental iron
- well absorbed**
- 325 mg tab- 65 mg elemental
-75mg/0.8 ml – 15 mg elemental
-15mg/ml- 15mg elemental
Ferrous gluconate
-12% elemental iron
-300 mg tab- 36 mg elemental
Carbonyl iron
-100% elemental iron
-15 mg tab
-15 mg/1.25 ml
-less absorption
Iron polysaccharide
-100% elemental iron
-100mg/5 ml, 150 mg tab
-well absorbed
Ferrous fumarate
-33% elemental iron
-200 mg tab- 66 mg elemental
-chewable tab 33 mg
-extended release tabs- poorer absorption
-Iron sprinkles (developing countries)
.
Oral iron therapyside effects
-BAD TASTE!
-GI intolerance
-Dark stools
-Staining of teeth
Response to Oral Iron
therapy
Monitoring:
1-2 weeks- (for moderate to severe
anemia)
-increase in reticulocyte count
- increase in hemoglobin (1-2
gm/dl)
4-6 weeks-correction of hemoglobin
Continue iron therapy for at least 3-4
months, possibly longer
Causes for poor
response to oral iron
-Non-compliance
***
-Incorrect administration***
-Incorrect diagnosis
-Incorrect dosing
-Ongoing blood loss
-Malabsorption
-IRIDA
Indications for IV iron
therapy
• Iron deficiency not responding to oral iron
therapy
-Poor compliance
-Adverse effects
-Malabsorption*
-Ongoing hemorrhage*
• Anemia of chronic disease (iron restricted
erythropoiesis)
-Renal failure, inflammatory disorders
.
IV iron therapy
Preparations:
• Iron dextran (HMW and LMW)
• Ferric gluconate
• Iron sucrose
Side effects:
• Anaphylaxis (2-3% with iron dextran)
• Chills, back pain, body aches
.
Neurodevelopmental
effects of ID and IDA
Psychomotor development and cognitive function
-MULTIPLE studies
-conflicting studies for ID
-moderate to severe IDA- long term decreased cognitive
function-may not recover with correction of iron status
Learning:
NHANES III- lower math scores with iron deficiency, no
effect seen with reading, verbal, and performance scores
Attention, concentration and cognitive function:
Meta-analysis of randomized trials in older children and
adults showed some improvement in attention,
concentration, and cognitive function with improvement in ID
Lozoff, et al. J Pediatr 1996; 129-382. Halterman et al. Pediatrics 2001; 107:1381. Lozoff et
al. Arch Pediatr Adolesc Med 2006; 160:1108. Falkinham et al. Nutr J 2010; 9:4.
Other Effects of ID and
IDA
• Changes in transmission through auditory
and visual systems in young infants
• Mild to moderate defects in leukocyte and
lymphocyte function
• Increased risk of cerebral vein thrombosis
• Breath holding spells
• Decreased exercise capacity
• PICA
• ? Febrile seizures
• Impaired myelination
• Neurotransmitter metabolism
.Algarin et al. BMJ 1996;313:343. Hartfield et al. Clin Pediatr (Phil) 2009; 48:420. Zehetner et
al. Cochrane Database Syst Rev 2010; :CD008132. Ekiz et al. Hematol J 2005; 5:579.
Benedict et al. J Chld Neurol 2004; 19;526.